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      Dantrolene rescues arrhythmogenic RYR2 defect in a patient-specific stem cell model of catecholaminergic polymorphic ventricular tachycardia

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          Abstract

          Coordinated release of calcium (Ca 2+) from the sarcoplasmic reticulum (SR) through cardiac ryanodine receptor (RYR2) channels is essential for cardiomyocyte function. In catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disease characterized by stress-induced ventricular arrhythmias in young patients with structurally normal hearts, autosomal dominant mutations in RYR2 or recessive mutations in calsequestrin lead to aberrant diastolic Ca 2+ release from the SR causing arrhythmogenic delayed after depolarizations (DADs). Here, we report the generation of induced pluripotent stem cells (iPSCs) from a CPVT patient carrying a novel RYR2 S406L mutation. In patient iPSC-derived cardiomyocytes, catecholaminergic stress led to elevated diastolic Ca 2+ concentrations, a reduced SR Ca 2+ content and an increased susceptibility to DADs and arrhythmia as compared to control myocytes. This was due to increased frequency and duration of elementary Ca 2+ release events (Ca 2+ sparks). Dantrolene, a drug effective on malignant hyperthermia, restored normal Ca 2+ spark properties and rescued the arrhythmogenic phenotype. This suggests defective inter-domain interactions within the RYR2 channel as the pathomechanism of the S406L mutation. Our work provides a new in vitro model to study the pathogenesis of human cardiac arrhythmias and develop novel therapies for CPVT.

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          Using iPS cells to investigate cardiac phenotypes in patients with Timothy Syndrome

          Masayuki Yazawa, Brian Hsueh, Xiaolin Jia … (2011)
          Individuals with congenital or acquired prolongation of the QT interval, or long QT syndrome (LQTS), are at risk of life threatening ventricular arrhythmia 1, 2. LQTS is commonly genetic in origin but can also be caused or exacerbated by environmental factors1, 3. A missense mutation in the L-type calcium channel CaV1.2 leads to LQTS in patients with Timothy syndrome (TS)4, 5. To explore the effect of the TS mutation on the electrical activity and contraction of human cardiomyocytes (CMs), we reprogrammed human skin cells from TS patients to generate induced pluripotent stem cells (iPSCs), and differentiated these cells into CMs. Electrophysiological recording and calcium (Ca2+) imaging studies of these cells revealed irregular contraction, excess Ca2+ influx, prolonged action potentials, irregular electrical activity and abnormal calcium transients in ventricular-like cells. We found that roscovitine (Ros), a compound that increases the voltage-dependent inactivation (VDI) of CaV1.26–8, restored the electrical and Ca2+ signaling properties of CMs from TS patients. This study opens new avenues for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans, and provides a robust assay for developing new drugs to treat these diseases.
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            Patient-specific induced pluripotent stem cell derived models of LEOPARD syndrome

            Xonia Carvajal-Vergara, Ana Sevilla, Sunita L. D’Souza … (2010)
            Generation of reprogrammed induced pluripotent stem cells (iPSC) from patients with defined genetic disorders promises important avenues to understand the etiologies of complex diseases, and the development of novel therapeutic interventions. We have generated iPSC from patients with LEOPARD syndrome (LS; acronym of its main features: Lentigines, Electrocardiographic abnormalities, Ocular hypertelorism, Pulmonary valve stenosis, Abnormal genitalia, Retardation of growth and Deafness), an autosomal dominant developmental disorder belonging to a relatively prevalent class of inherited RAS-MAPK signaling diseases, which also includes Noonan syndrome (NS), with pleiomorphic effects on several tissues and organ systems1,2. The patient-derived cells have a mutation in the PTPN11 gene, which encodes the SHP2 phosphatase. The iPSC have been extensively characterized and produce multiple differentiated cell lineages. A major disease phenotype in patients with LEOPARD syndrome is hypertrophic cardiomyopathy. We show that in vitro-derived cardiomyocytes from LS-iPSC are larger, have a higher degree of sarcomeric organization and preferential localization of NFATc4 in the nucleus when compared to cardiomyocytes derived from human embryonic stem cells (HESC) or wild type (wt) iPSC derived from a healthy brother of one of the LS patients. These features correlate with a potential hypertrophic state. We also provide molecular insights into signaling pathways that may promote the disease phenotype.
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              Leaky Ca2+ release channel/ryanodine receptor 2 causes seizures and sudden cardiac death in mice.

              Stephan Lehnart, Marco Mongillo, Andrew Bellinger … (2008)
              The Ca2+ release channel ryanodine receptor 2 (RyR2) is required for excitation-contraction coupling in the heart and is also present in the brain. Mutations in RyR2 have been linked to exercise-induced sudden cardiac death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). CPVT-associated RyR2 mutations result in "leaky" RyR2 channels due to the decreased binding of the calstabin2 (FKBP12.6) subunit, which stabilizes the closed state of the channel. We found that mice heterozygous for the R2474S mutation in Ryr2 (Ryr2-R2474S mice) exhibited spontaneous generalized tonic-clonic seizures (which occurred in the absence of cardiac arrhythmias), exercise-induced ventricular arrhythmias, and sudden cardiac death. Treatment with a novel RyR2-specific compound (S107) that enhances the binding of calstabin2 to the mutant Ryr2-R2474S channel inhibited the channel leak and prevented cardiac arrhythmias and raised the seizure threshold. Thus, CPVT-associated mutant leaky Ryr2-R2474S channels in the brain can cause seizures in mice, independent of cardiac arrhythmias. Based on these data, we propose that CPVT is a combined neurocardiac disorder in which leaky RyR2 channels in the brain cause epilepsy, and the same leaky channels in the heart cause exercise-induced sudden cardiac death.
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                Author and article information

                Journal
                Journal ID (nlm-ta): EMBO Mol Med
                Journal ID (iso-abbrev): EMBO Mol Med
                Journal ID (publisher-id): emmm
                Title: EMBO Molecular Medicine
                Publisher: WILEY-VCH Verlag (Weinheim )
                ISSN (Print): 1757-4676
                ISSN (Electronic): 1757-4684
                Publication date (Print): March 2012
                Volume: 4
                Issue: 3
                Pages: 180-191
                Affiliations
                [1 ]simpleKlinikum rechts der Isar, Technische Universität München, I. Medizinische Klinik, Kardiologie München, Germany
                [2 ]simpleDeutsches Herzzentrum, Technische Universität München, Erwachsenenkardiologie München, Germany
                [3 ]simpleWalther-Straub-Institut für Pharmakologie and Toxikologie, Ludwig-Maximilians Universität München Goethetraße, München, Germany
                [4 ]simpleInstitut für Molekulare Zellbiologie, Medizinische Fakultät, Universitätsklinikum Homburg/Saar, Universität des Saarlandes Homburg/Saar, Germany
                [5 ]simpleHelios Klinikum Wuppertal-Universität Witten-Herdecke, III. Medizinische Klinik Kardiologie, Wuppertal, Germany
                Author notes
                * Corresponding author: Tel: +49 89 41402947; Fax: +49 89 41404901; E-mail: klaugwitz@ 123456med1.med.tum.de
                ** Corresponding author: Tel: +49 6841 1626103; Fax: +49 6841 1626104; E-mail: peter.lipp@ 123456uniklinikum-saarland.de
                *** Corresponding author: Tel: +49 89 218075702; Fax: +49 89 218075701; E-mail: thomas.gudermann@ 123456lrz.uni-muenchen.de
                [†]

                These authors contributed equally to this work.

                Article
                DOI: 10.1002/emmm.201100194
                PMC ID: 3376852
                PubMed ID: 22174035
                SO-VID: 9e78949f-3cad-4524-84d3-6e3e26e6af59
                Copyright © Copyright © 2012 EMBO Molecular Medicine
                History
                Date received : 30 August 2011
                Date revision received : 01 December 2011
                Date accepted : 05 December 2011
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Molecular medicine
                Keywords: disease modelling,induced pluripotent stem cells,dantrolene,cpvt,ryanodine receptor 2
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: disease modelling, induced pluripotent stem cells, dantrolene, cpvt, ryanodine receptor 2

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